Histone deacetylase 10 structure and molecular function as a polyamine deacetylase
Open accessAbstract
Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that histone deacetylase 10 (HDAC10) is a robust polyamine deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.
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Written from the paper’s full text.
TL;DR
HDAC10 is a robust polyamine deacetylase with optimal specificity for N8-acetylspermidine hydrolysis, not an efficient lysine deacetylase. The 2.85 Å crystal structure shows that gatekeeper E274 and a sterically constricted active site, including the 3₁₀-helix ηA2, confer this substrate specificity.
Key findings
- Recombinant human and zebrafish HDAC10 hydrolyzed N8-acetylspermidine with kcat/KM = 2,900 ± 200 and 4,600 ± 300 M−1 s−1, respectively; N1-acetylspermidine was a poor substrate with kcat/KM = 24 ± 5 and 7 ± 2 M−1 s−1.
- HDAC10 showed very low activity against acetyllysine substrates, including GAK(ac)-AMC, RGK(ac)-AMC, and 11 non-fluorogenic acetyllysine substrates; HDAC6 preferred RGK(ac)-AMC >100-fold over N8-acetylspermidine.
- The E274L mutation in zebrafish HDAC10 diminished N8-acetylspermidine deacetylase activity by 20-fold and enhanced acetyllysine deacetylase activity by ∼100-fold, reversing substrate specificity.
- The 2.85 Å crystal structure of Y307F zHDAC10Δ complexed with the transition-state analogue AAT (Ki = 0.7 ± 0.2 μM) revealed a constricted active site; removal of the 3₁₀-helix ηA2 insertion decreased PDAC activity 15-fold and increased HDAC activity 16-fold.
Methods
- Full-length recombinant human and zebrafish HDAC10, mutants, HDAC6, and APAH were expressed and purified; steady-state kinetics were measured in triplicate using fluorogenic acetyllysine peptides and a discontinuous LC–MS assay for non-fluorogenic peptides and acetylpolyamines.
- The Y307F zHDAC10Δ–AAT complex was crystallized, X-ray diffraction data were collected at Stanford Synchrotron Radiation Lightsource beamline 14-1, and the structure was solved by molecular replacement and refined; coordinates were deposited under PDB 5TD7.
- Additional analyses included electrostatic surface potential calculations, ConSurf residue conservation across 250 HDAC10 orthologues, phylogenetic tree construction, and a model of the zHDAC10–substrate complex.
Limitations
- The paper states that no statistical methods were used to predetermine sample size; it also states that it cannot comment on Hsc70/Hsp70 deacetylation because it is not characterized at the molecular level, and that MSH2 K73 deacetylation has not been directly demonstrated by enzyme catalysis.
- Evident from the text: the crystal structure is of zebrafish Y307F zHDAC10Δ, not human HDAC10, and the interdomain linker was missing in the electron density due to proteolysis; the AAT terminal amino group was disordered.
- Evident from the text: the study reports in vitro enzymology and structural analysis, with no cellular autophagy experiments or inhibitor efficacy data.
Model-written summary. Check it against the paper before relying on it.
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- Findingown data
The crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor was determined at 2.85 Å resolution.
“we determined the 2.85 Å-resolution crystal structure of Y307F zHDAC10 complexed with the trifluoromethylketone inhibitor 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptan-2-one (AAT, Supplementary Fig. 2), which mimics N8-acetylspermidine24.”
Quote in the paperSubstantial claim- Rests on an assumption: The Y307F mutation and proteolytic truncation used to crystallize zHDAC10 do not alter the active-site structure or substrate specificity determinants observed in the crystal structure.
- Findingown data
For hHDAC10 and zHDAC10, kcat/KM for N8-acetylspermidine hydrolysis is 2,900±200 and 4,600±300 M−1 s−1, respectively.
“For hHDAC10 and zHDAC10, kcat/KM=2,900±200 and 4,600±300 M−1 s−1, respectively; in comparison, N1-acetylspermidine was a poor substrate with kcat/KM=24±5 and 7±2 M−1 s−1, respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingcitation
HDAC6 preferentially catalyses deacetylation of RGK(ac)-AMC with catalytic efficiency >100-fold greater than deacetylation of N8-acetylspermidine.
“HDAC6 preferentially catalyses the deacetylation of the peptide substrate RGK(ac)-AMC with a catalytic efficiency >100-fold greater than that for the deacetylation of N8-acetylspermidine.”
Quote in the paperSubstantial claim - Findingown data
The N4 amino group of N8-acetylspermidine is required for optimal activity.
“The N4 amino group of N8-acetylspermidine was required for optimal activity in comparison with N-(8-aminooctyl)acetamide, which lacks the secondary amino group.”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
For hHDAC10 and zHDAC10, N1-acetylspermidine is a poor substrate with kcat/KM=24±5 and 7±2 M−1 s−1, respectively.
“For hHDAC10 and zHDAC10, kcat/KM=2,900±200 and 4,600±300 M−1 s−1, respectively; in comparison, N1-acetylspermidine was a poor substrate with kcat/KM=24±5 and 7±2 M−1 s−1, respectively.”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
The crystal structure of Y307F zHDAC10Δ-AAT complex revealed an overall butterfly-like architecture with a pseudo-two-fold symmetry axis perpendicular to several α-helices defining the PDAC-ΨDAC domain interface.
“The crystal structure of the Y307F zHDAC10Δ–AAT complex (Fig. 3a) revealed an overall butterfly-like architecture with a pseudo-two-fold symmetry axis perpendicular to several α-helices defining the PDAC-ΨDAC domain interface.”
Quote in the paperSubstantial claim- Rests on an assumption: The Y307F mutation and proteolytic truncation used to crystallize zHDAC10 do not alter the active-site structure or substrate specificity determinants observed in the crystal structure.
- Findingown data
hHDAC10 and zHDAC10 exhibited no or very low catalytic activity with 11 non-fluorogenic acetyllysine substrates, including K(ac)NL and GAK(ac)NLQ.
“Again, we observed no or very low catalytic activity (Fig. 2 and Supplementary Table 1).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
Both hHDAC10 and zHDAC10 exhibited optimal catalytic activity and specificity for hydrolysis of N8-acetylspermidine.
“Both enzymes exhibited optimal catalytic activity and specificity for the hydrolysis of N8-acetylspermidine.”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
The 2.85 Å-resolution crystal structure of Y307F zHDAC10 complexed with AAT was determined.
“To provide a molecular foundation for understanding the PDAC activity of HDAC10, we determined the 2.85 Å-resolution crystal structure of Y307F zHDAC10 complexed with the trifluoromethylketone inhibitor 7-[(3-aminopropyl)amino]-1,1,1-trifluoroheptan-2-one (AAT, Supplementary Fig. 2), which mimics N8-acetylspermidine24.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Decroos, C., Bowman, C. M. & Christianson, D. W. Synthesis and evaluation of N8-acetylspermidine analogues as inhibitors of bacterial acetylpolyamine amidohydrolase. Bioorg. Med. Chem. 21, 4530–4540 (2013). source
Not checked in the free run.
- Rests on an assumption: The Y307F mutation and proteolytic truncation used to crystallize zHDAC10 do not alter the active-site structure or substrate specificity determinants observed in the crystal structure.
- Findingown data
The proteolytically nicked zHDAC10Δ construct retains substantial catalytic activity.
“The proteolytically nicked zHDAC10Δ construct retains substantial catalytic activity (Supplementary Table 1).”
Quote in the paperNot a substantial claim - Findingown data
Both hHDAC10 and zHDAC10 exhibited very low activity with AMC-conjugated acetyllysine peptides GAK(ac)-AMC and RGK(ac)-AMC.
“Both hHDAC10 and zHDAC10 exhibited very low activity with these peptides (Fig. 2 and Supplementary Table 1).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
The MSH2-based substrate GAK(ac)NLQ is efficiently deacetylated by HDAC6.
“Intriguingly, however, we demonstrated that the MSH2-based substrate GAK(ac)NLQ is efficiently deacetylated by HDAC6 (Supplementary Table 1 and Supplementary Fig. 3), which is also known to interact with and deacetylate MSH2 in vivo33.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Zhang, M. et al. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol. Cell 55, 31–46 (2014). source
Not checked in the free run.
- Findingown data
The ΨDAC domain lacked helices ηA1-A2, αA, αB2-αB3 and active site loops L1-L5.
“However, the ΨDAC domain lacked helices ηA1–A2, αA, αB2–αB3 and active site loops L1–L5 (Fig. 3b).”
Quote in the paperSubstantial claim - Findingown data
The closest relationship between the HDAC and arginase families is between the ΨDAC domain of Cavia porcellus HDAC10 and H. sapiens agmatinase (sequence identity=19%).
“Our phylogenetic analysis (Fig. 6) indicated that the closest relationship between the HDAC and arginase families is between the ΨDAC domain of Cavia porcellus HDAC10 and H. sapiens agmatinase (sequence identity=19%).”
Quote in the paperNot a substantial claim - Findingown data
The tertiary structure of the HDAC10 PDAC domain is similar to CD1 and CD2 of HDAC6 (0.78 Å r.m.s.d. for 355 Cα atoms; 0.88 Å r.m.s.d. for 352 Cα atoms, zCD2).
“The tertiary structure of the PDAC domain was similar to both CD1 (PDB 5EEF) and CD2 (PDB 5EFH) of HDAC6 (0.78 Å root mean squared deviation (r.m.s.d.) for 355 Cα atoms; 0.88 Å r.m.s.d. for 352 Cα atoms, zCD2) (Fig. 3c).”
Quote in the paperSubstantial claim - Findingown data
The surface of the HDAC10 PDAC domain becomes less anionic and ultimately cationic at the base of the active site tunnel.
“However, the surface of the HDAC10 PDAC domain became less anionic and ultimately cationic, at the base of the active site tunnel (Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
Gatekeeper E274 is close (3.7 Å) to the N4 atom of AAT.
“On one side of the active site, gatekeeper E274 was close (3.7 Å) to the N4 atom of AAT (Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
The four-residue segment containing ηA2 is universally conserved in HDAC10 orthologues with only minor variations, appearing predominantly as PECE.
“This four-residue segment is universally conserved in HDAC10 orthologues with only minor variations, appearing predominantly as PECE (Supplementary Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
The HDAC10 active site is much more constricted compared with other isozymes such as HDAC6.
“The structure of zHDAC10 allowed us to study substrate specificity determinants: in particular, the active site was much more constricted compared with other isozymes such as HDAC6.”
Quote in the paperSubstantial claim - Findingown data
Neither N93A nor D94A mutant exhibited substantial differences in steady-state kinetic parameters.
“Neither mutant exhibited substantial differences in steady-state kinetic parameters (Supplementary Table 1 and Supplementary Fig. 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
The active site tunnel in the HDAC10 PDAC domain is surrounded by a vast surface of negative electrostatic potential, resulting in large part from conserved aspartate and glutamate residues.
“The active site tunnel in the PDAC domain was surrounded by a vast surface of negative electrostatic potential (Fig. 5a,b and Supplementary Fig. 6), resulting in large part from conserved aspartate and glutamate residues (Supplementary Fig. 1).”
Quote in the paperSubstantial claim - Findingcitation
The AAT binding mode in HDAC10 is similar to that observed in APAH-AAT and zHDAC6 CD2-AAT complexes.
“This binding mode was similar to that observed in the APAH–AAT and zHDAC6 CD2–AAT complexes1729.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17] Hai, Y. & Christianson, D. W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12, 741–747 (2016). source
Not checked in the free run.
- cites [29] Decroos, C. & Christianson, D. W. Design, synthesis, and evaluation of polyamine deacetylase inhibitors, and high-resolution crystal structures of their complexes with acetylpolyamine amidohydrolase. Biochemistry 54, 4692–4703 (2015). source
Not checked in the free run.
- Findingown data
Interdomain interactions in HDAC10 were mediated by α-helices αF and αG, loop LH, and the C-terminal tail of each domain, burying ∼1,700 Å2 surface area.
“Interdomain interactions were mediated by α-helices αF and αG, loop LH (which connects αH1 and αH2) and the C-terminal tail of each domain, burying ∼1,700 Å2 surface area.”
Quote in the paperNot a substantial claim - Findingown data
HDAC10 does not catalyse the deacetylation of MSH2-based peptide substrates K(ac)NL and GAK(ac)NLQ.
“moreover, our steady-state kinetic measurements showed that HDAC10 does not catalyse the deacetylation of MSH2-based peptide substrates K(ac)NL and GAK(ac)NLQ (Supplementary Table 1).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Findingown data
Opposite E274, a unique one-turn 310-helix ηA2 (P23ACE) resulting from a two-residue insertion plus a two-residue mutation in the L1 loop relative to zHDAC6 effectively lengthens the narrow active site tunnel by ∼5 Å.
“Opposite E274, there was an additional constriction contributing to PDAC specificity: a unique one-turn 310-helix ηA2 (P23ACE) resulting from a two-residue insertion plus a two-residue mutation in the L1 loop relative to zHDAC6, effectively lengthening the narrow active site tunnel by ∼5 Å (Fig. 3c,d).”
Quote in the paperSubstantial claim - Findingown data
The PDAC and ΨDAC domains of zHDAC10 did not dissociate upon proteolytic nicking of the interdomain linker.
“(the PDAC-ΨDAC domains did not dissociate upon proteolytic nicking of the interdomain linker)”
Quote in the paperNot a substantial claim - Findingown data
The PDAC domain (residues 2-370) of zHDAC10 remained intact after proteolytic nicking, as determined by LC-MS/MS.
“The PDAC domain (residues 2–370) remained intact after proteolytic nicking as determined by LC–MS/MS.”
Quote in the paperSubstantial claim - Interpretationown data
The single-point mutation E274L completely reversed the substrate specificity of zHDAC10, converting it from a PDAC into an HDAC.
“Thus, the single-point mutation E274L completely reversed the substrate specificity of zHDAC10, converting it from a PDAC into an HDAC (Fig. 2c).”
Quote in the paperSubstantial claim - Interpretationreasoning
The molecular function of HDAC10 coincides with the cellular function of the cytosolic PDAC indicated in Fig. 1a.
“It is notable that the molecular function of HDAC10 coincides with the cellular function of the cytosolic PDAC indicated in Fig. 1a.”
Quote in the paperNot a substantial claim - Premisecitation
HDAC10 is enriched in the cytoplasm.
“HDAC10 is highly expressed in the liver, spleen and kidney1819, enriched in the cytoplasm19 and resistant to inhibition by sodium butyrate20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Tong, J. J., Liu, J., Bertos, N. R. & Yang, X. J. Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain. Nucleic Acids Res. 30, 1114–1123 (2002). source
Not checked in the free run.
- Premisecitation
HDAC10 is highly expressed in the liver, spleen and kidney.
“HDAC10 is highly expressed in the liver, spleen and kidney1819, enriched in the cytoplasm19 and resistant to inhibition by sodium butyrate20.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Kao, H.-Y., Lee, C.-H., Komarov, A., Han, C. C. & Evans, R. M. Isolation and characterization of mammalian HDAC10, a novel histone deacetylase. J. Biol. Chem. 277, 187–193 (2002). source
Not checked in the free run.
- cites [19] Tong, J. J., Liu, J., Bertos, N. R. & Yang, X. J. Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain. Nucleic Acids Res. 30, 1114–1123 (2002). source
Not checked in the free run.
- Premisecitation
Each HDAC10 domain adopted the α/β-fold first observed in arginase and subsequently in the HDAC family.
“Each domain adopted the α/β-fold first observed in the crystal structure of arginase25 and subsequently observed in the HDAC family26.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25] Kanyo, Z. F., Scolnick, L. R., Ash, D. E. & Christianson, D. W. Structure of a unique binuclear manganese cluster in arginase. Nature 383, 554–557 (1996). source
Not checked in the free run.
- cites [26] Finnin, M. S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999). source
Not checked in the free run.
- Premisecitation
HDAC10 is resistant to inhibition by sodium butyrate.
“HDAC10 is highly expressed in the liver, spleen and kidney1819, enriched in the cytoplasm19 and resistant to inhibition by sodium butyrate20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Guardiola, A. R. & Yao, T.-P. Molecular cloning and characterization of a novel histone deacetylase HDAC10. J. Biol. Chem. 277, 3350–3356 (2002). source
Not checked in the free run.
- Interpretationown data
The ideal length of a PDAC substrate ranges 8-12 atoms long.
“These results suggested that the ideal length of a PDAC substrate ranged 8–12 atoms long.”
Quote in the paperSubstantial claim - Interpretationown data
HDAC10 is not an efficient lysine deacetylase compared with HDAC6.
“In comparison with its closest relative, the cytosolic isozyme HDAC6 (ref. 17), HDAC10 was clearly not an efficient lysine deacetylase.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Hai, Y. & Christianson, D. W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12, 741–747 (2016). source
Not checked in the free run.
- Premisecitation
Selective inhibitors have been developed that block mammalian PDAC activity.
“However, selective inhibitors have been developed that block mammalian PDAC activity111213.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [11] Marchant, P. et al. A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation. Arch. Biochem. Biophys. 273, 128–136 (1989). source
Not checked in the free run.
- cites [12] Dredar, S. A., Blankenship, J. W., Marchant, P. E., Manneh, V. & Fries, D. S. Design and synthesis of inhibitors of N8-acetylspermidine deacetylase. J. Med. Chem. 32, 984–989 (1989). source
Not checked in the free run.
- cites [13] Huang, T. L., Dredar, S. A., Manneh, V. A., Blankenship, J. W. & Fries, D. S. Inhibition of N8-acetylspermidine deacetylase by active-site-directed metal coordinating inhibitors. J. Med. Chem. 35, 2414–2418 (1992). source
Not checked in the free run.
- Premisecitation
PDAC substrate specificity is very strict; it does not deacetylate cytosolic N1-acetylspermidine or N1-acetylspermine.
“The substrate specificity of PDAC is very strict, as it does not deacetylate cytosolic N1-acetylspermidine or N1-acetylspermine10.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Marchant, P., Manneh, V. A. & Blankenship, J. N1-Acetylspermidine is not a substrate for N-acetylspermidine deacetylase. Biochim. Biophys. Acta 881, 297–299 (1986). source
Not checked in the free run.
- Premiseown data
In all other human HDACs, the gatekeeper residue is conserved as leucine or methionine, except HDAC10 in which it is a glutamate.
“In all other human HDACs, this residue is otherwise conserved as leucine or methionine, except for HDAC10 in which it is a glutamate (Fig. 1b and Supplementary Fig. 1).”
Quote in the paperSubstantial claim - Interpretationown data
Substrate specificity trends observed for zHDAC10 and hHDAC10 matched those of previously reported mammalian N8-acetylspermidine deacetylase activity.
“Substrate specificity trends observed for zHDAC10 and hHDAC10 matched those of the previously reported mammalian N8-acetylspermidine deacetylase activity91011.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9] Libby, P. R. Properties of an acetylspermidine deacetylase from rat liver. Arch. Biochem. Biophys. 188, 360–363 (1978). source
Not checked in the free run.
- cites [10] Marchant, P., Manneh, V. A. & Blankenship, J. N1-Acetylspermidine is not a substrate for N-acetylspermidine deacetylase. Biochim. Biophys. Acta 881, 297–299 (1986). source
Not checked in the free run.
- cites [11] Marchant, P. et al. A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation. Arch. Biochem. Biophys. 273, 128–136 (1989). source
Not checked in the free run.
- Interpretationreasoning
Identical α/β-folds and conservation of metal binding sites suggest that HDACs and arginases divergently evolved from a common primordial ancestor.
“However, identical α/β-folds (β-strand order 21387456) and the conservation of metal binding sites (the Mn2+B site of arginases is conserved as the Zn2+ site of HDACs) suggest that HDACs and arginases divergently evolved from a common primordial ancestor.”
Quote in the paperSubstantial claim - Interpretationown data
The in vitro results are more consistent with HDAC6 being the MSH2 deacetylase.
“Our in vitro results are more consistent with HDAC6 being the MSH2 deacetylase.”
Quote in the paperSubstantial claim - Interpretationown data
The binding of AAT mimics the tetrahedral intermediate and flanking transition states for hydrolysis of N8-acetylspermidine.
“The binding of AAT thus mimicked the tetrahedral intermediate and its flanking transition states for the hydrolysis of N8-acetylspermidine.”
Quote in the paperSubstantial claim - Interpretationreasoning
Binding of N1-acetylspermidine would place the positively charged N4 amino group closer to this cationic surface, which would disfavour N1-acetylspermidine binding relative to N8-acetylspermidine binding.
“The binding of N1-acetylspermidine would place the positively charged N4 amino group closer to this cationic surface, which would disfavour N1-acetylspermidine binding relative to N8-acetylspermidine binding.”
Quote in the paperSubstantial claim - Interpretationown data
Neither N93 nor D94 are required for enzyme-substrate recognition and catalysis in zHDAC10.
“Thus, neither N93 nor D94 are required for enzyme–substrate recognition and catalysis.”
Quote in the paperSubstantial claim - Interpretationreasoning
The gatekeeper appears to be a 'hot spot' for dictating substrate specificity.
“Regardless, the gatekeeper appears to be a ‘hot spot' for dictating substrate specificity.”
Quote in the paperSubstantial claim - Interpretationreasoning
The E274L mutation demonstrated that the electrostatic interaction between E274 and substrate is important for PDAC specificity.
“The conversion of HDAC10 from a PDAC into an HDAC through the E274L mutation (Fig. 2) demonstrated that this electrostatic interaction is important for PDAC specificity.”
Quote in the paperSubstantial claim - Interpretationown data
The evolution of PDAC activity in vertebrate HDAC10 and the bacterial deacetylase APAH occurred convergently.
“Interestingly, this analysis also suggested that the evolution of PDAC activity in vertebrate HDAC10 and the bacterial deacetylase APAH occurred convergently.”
Quote in the paperNot a substantial claim - Premisecitation
HDACs adopt the same α/β-fold first observed in the crystal structure of arginase, a binuclear manganese metalloenzyme that catalyses hydrolysis of arginine to ornithine plus urea.
“As previously mentioned, HDACs adopt the same α/β-fold first observed in the crystal structure of arginase, a binuclear manganese metalloenzyme that catalyses the hydrolysis of arginine to form ornithine plus urea1525.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Ash, D. E., Cox, J. D. & Christianson, D. W. Arginase: a binuclear manganese metalloenzyme. Metal Ions Biol. Syst. 37, 407–428 (2000).
Not checked in the free run.
- cites [25] Kanyo, Z. F., Scolnick, L. R., Ash, D. E. & Christianson, D. W. Structure of a unique binuclear manganese cluster in arginase. Nature 383, 554–557 (1996). source
Not checked in the free run.
- Premisecitation
D94 corresponds to acetyllysine binding residues D101 of hHDAC8 and S568 of hHDAC6 CD2.
“Interestingly, D94 corresponds to acetyllysine binding residues D101 of hHDAC8 and S568 of hHDAC6 CD2 (refs 17, 30, 31).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [17] Hai, Y. & Christianson, D. W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12, 741–747 (2016). source
Not checked in the free run.
- cites [30] Dowling, D. P., Gantt, S. L., Gattis, S. G., Fierke, C. A. & Christianson, D. W. Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors. Biochemistry 47, 13554–13563 (2008). source
Not checked in the free run.
- cites [31] Vannini, A. et al. Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Rep. 8, 879–884 (2007). source
Not checked in the free run.
- Interpretationcitation
Polyamine metabolism is closely linked to autophagy.
“Thus, polyamine metabolism is closely linked to autophagy.”
Quote in the paperNot a substantial claim - Interpretationcitation
HDAC10 is an emerging target for treatment of advanced-stage neuroblastoma.
“As the suppression of autophagy to sustain the cytotoxicity of chemotherapeutic drugs is a novel strategy for cancer chemotherapy3435, HDAC10 is an emerging target for the treatment of advanced-stage neuroblastoma32.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [32] Oehme, I. et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl Acad. Sci. USA 110, E2592–E2601 (2013). source
Not checked in the free run.
- cites [34] Høyer-Hansen, M. & Jäättelä, M. Autophagy: an emerging target for cancer therapy. Autophagy 4, 574–580 (2008). source
Not checked in the free run.
- cites [35] Lefranc, F., Facchini, V. & Kiss, R. Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 12, 1395–1403 (2007). source
Not checked in the free run.
- May combine two claims. 34
- Classified as probably not a substantial claim. 15
May combine two claims.
Findingown dataHDAC10 is a robust polyamine deacetylase and a poor lysine deacetylase.
“Here we report that histone deacetylase 10 (HDAC10) is a robust polyamine deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish).”
- Also stated in: § Abstract · boosted
“Here we report enzymological studies conclusively demonstrating that HDAC10 is a robust PDAC and a poor lysine deacetylase.”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
- Also stated in: § Abstract · boosted
May combine two claims.
Findingown dataHDAC10 exhibits substantial catalytic activity with acetylcadaverine, acetylputrescine, and N-(8-aminooctyl)acetamide, but minimal or no activity with N-butylacetamide and N-(3-aminopropyl)acetamide.
“Although the PDAC activity of zHDAC10 and hHDAC10 was highest with N8-acetylspermidine, substantial catalytic activity was also observed with acetylcadaverine and acetylputrescine, as well as N-(8-aminooctyl)acetamide; in contrast, the shorter substrates N-butylacetamide and N-(3-aminopropyl)acetamide exhibited minimal or no activity, respectively (Fig. 2).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
May combine two claims.
Findingown dataAAT binds zHDAC10 as a transition state analogue with Ki=0.7±0.2 μM.
“This inhibitor binds as a transition state analogue with Ki=0.7±0.2 μM (Supplementary Fig. 4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBacterial PDAC APAH exhibits broad substrate specificity with all polyamine substrates except N-butylacetamide and weak lysine deacetylase activity.
“In comparison with HDAC10, the bacterial PDAC APAH exhibited broad substrate specificity with all polyamine substrates except for N-butylacetamide; it also exhibited weak lysine deacetylase activity (Supplementary Table 1 and Supplementary Fig. 3).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataE274L substitution in zHDAC10 diminishes N8-acetylspermidine deacetylase activity by 20-fold and enhances acetyllysine deacetylase activity by ∼100-fold.
“In accord with our hypothesis, this substitution diminished N8-acetylspermidine deacetylase activity by 20-fold and enhanced acetyllysine deacetylase activity by ∼100-fold (Supplementary Fig. 3 and Supplementary Table 1).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
May combine two claims.
Findingown dataRemoval of the 310-helix ηA2 insertion yielded zHDAC10 ΔηA2, which exhibited 15-fold decreased PDAC activity and 16-fold increased HDAC activity.
“Removal of the 310-helix ηA2 insertion yielded construct zHDAC10 ΔηA2, which exhibited 15-fold decreased PDAC activity and 16-fold increased HDAC activity (Supplementary Table 1, Fig. 2 and Supplementary Fig. 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
May combine two claims.
FindingcitationHDAC10 PDAC-ΨDAC heterodomain assembly resembles HDAC6 heterodomain assembly and HDAC homodomain assembly in Schizosaccharomyces pombe Clr3.
“HDAC10 PDAC-ΨDAC heterodomain assembly resembles HDAC6 heterodomain assembly and HDAC homodomain assembly in Schizosaccharomyces pombe Clr3 (Supplementary Fig. 5)2728.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Miyake, Y. et al. Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nat. Chem. Biol. 12, 748–754 (2016). source
Not checked in the free run.
- cites [28] Job, G. et al. SHREC silences heterochromatin via distinct remodeling and deacetylation modules. Mol. Cell 62, 207–221 (2016). source
Not checked in the free run.
May combine two claims.
Findingown dataThe primary amino group at the end of AAT is disordered in the crystal structure but would be located near the side chains of N93, D94 and A24.
“The crystal structure of the Y307F zHDAC10Δ–AAT complex revealed that the primary amino group at the end of AAT is disordered (Fig. 3d), but it would be located near the side chains of N93, D94 and A24.”
Quote in the paperNot a substantial claim- Rests on an assumption: The Y307F mutation and proteolytic truncation used to crystallize zHDAC10 do not alter the active-site structure or substrate specificity determinants observed in the crystal structure.
May combine two claims.
Findingown dataThe trifluoroketone moiety of AAT formed a gem-diolate, making asymmetric coordination interactions with Zn2+ (O1-Zn2+ and O2-Zn2+ distances 2.1 and 2.5 Å), and O2 hydrogen bonded with H136 and H137.
“The trifluoroketone moiety of AAT formed a gem-diolate, making asymmetric coordination interactions with Zn2+ (O1-Zn2+ and O2-Zn2+ coordination distances of 2.1 and 2.5 Å, respectively); hydroxyl group O2 also hydrogen bonded with H136 and H137.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataα-helices αG and αH at the interdomain interface are highly conserved.
“however, α-helices αG and αH at the interdomain interface were highly conserved (Supplementary Fig. 5).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNeither the Zn2+ ligands nor catalytic residues were conserved in the ΨDAC domain.
“Neither the Zn2+ ligands nor catalytic residues were conserved in the ΨDAC domain (Fig. 3b).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationIn zHDAC10, the 310-helix ηA2 provides the additional steric bulk; in hHDAC6 CD1, F105 and Y225 provide this steric bulk.
“In zHDAC10, the 310-helix ηA2 provides this steric bulk; in hHDAC6 CD1 (ref. 17), F105 and Y225 provide this steric bulk.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Hai, Y. & Christianson, D. W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12, 741–747 (2016). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe 48-residue linker was missing in the electron density, presumably due to proteolysis.
“The 48-residue linker was missing in the electron density, presumably due to proteolysis.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThis electrostatic surface feature is unique to HDAC10 orthologues and contrasts with that of the lysine deacetylase HDAC6 CD2.
“This electrostatic surface feature is unique to HDAC10 orthologues and contrasts with that of the lysine deacetylase HDAC6 CD2 (Fig. 5c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe HDAC10 active site tunnel contains a canonical HDAC active site at its base, with AAT binding in an extended conformation.
“A close-up view of the active site tunnel revealed a canonical HDAC active site at the base of the tunnel, with AAT binding in an extended conformation (Fig. 3d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe overall fold of the ΨDAC domain is most similar to that of the PDAC domain, as well as the CDs of HDAC6 (∼2.1 Å r.m.s.d. for ∼213 Cα atoms in each).
“The overall fold of the ΨDAC domain was most similar to that of the PDAC domain, as well as the CDs of HDAC6 (∼2.1 Å r.m.s.d. for ∼213 Cα atoms in each).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataA glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis.
“The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis.”
Quote in the paperSubstantial claim- Rests on an assumption: The Y307F mutation and proteolytic truncation used to crystallize zHDAC10 do not alter the active-site structure or substrate specificity determinants observed in the crystal structure.
May combine two claims.
PremisecitationSpermidine is acetylated at N8 by an N-acetyltransferase in the nucleus and then exported to the cytosol, where it is deacetylated by a metal-dependent N8-acetylspermidine deacetylase (PDAC).
“Spermidine is acetylated at the N8 position by an N-acetyltransferase in the cell nucleus7 and then exported to the cytosol, where it is deacetylated by a metal-dependent N8-acetylspermidine deacetylase, also known as polyamine deacetylase (PDAC)89.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] Libby, P. R. Rat liver nuclear N-acetyltransferases: separation of two enzymes with both histone and spermidine acetyltransferase activity. Arch. Biochem. Biophys. 203, 384–389 (1980). source
Not checked in the free run.
- cites [8] Blankenship, J. Deacetylation of N8-acetylspermidine by subcellular fractions of rat tissue. Arch. Biochem. Biophys. 189, 20–27 (1978). source
Not checked in the free run.
- cites [9] Libby, P. R. Properties of an acetylspermidine deacetylase from rat liver. Arch. Biochem. Biophys. 188, 360–363 (1978). source
Not checked in the free run.
May combine two claims.
PremisecitationBoth HDAC10 and spermidine promote cellular survival through autophagy.
“Both HDAC10 and spermidine are known to promote cellular survival through autophagy.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [32] Oehme, I. et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl Acad. Sci. USA 110, E2592–E2601 (2013). source
Not checked in the free run.
- cites [36] Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009). source
Not checked in the free run.
- cites [37] Minois, N. Molecular basis of the 'anti-aging' effect of spermidine and other natural polyamines – a mini-review. Gerontology 60, 319–326 (2014). source
Not checked in the free run.
May combine two claims.
Interpretationown dataHDAC6 is an acetyllysine deacetylase and HDAC10 is an N8-acetylspermidine deacetylase.
“Therefore, HDAC6 is clearly an acetyllysine deacetylase and HDAC10 is an N8-acetylspermidine deacetylase.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThese properties match the tissue distribution, subcellular localization and inhibitor sensitivity of mammalian PDAC.
“These properties match the tissue distribution, subcellular localization and inhibitor sensitivity of mammalian PDAC8910111213.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Blankenship, J. Deacetylation of N8-acetylspermidine by subcellular fractions of rat tissue. Arch. Biochem. Biophys. 189, 20–27 (1978). source
Not checked in the free run.
- cites [9] Libby, P. R. Properties of an acetylspermidine deacetylase from rat liver. Arch. Biochem. Biophys. 188, 360–363 (1978). source
Not checked in the free run.
- cites [10] Marchant, P., Manneh, V. A. & Blankenship, J. N1-Acetylspermidine is not a substrate for N-acetylspermidine deacetylase. Biochim. Biophys. Acta 881, 297–299 (1986). source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationHDAC6 catalytic domain CD1 has a conserved active site lysine gatekeeper that dictates specificity for carboxy-terminal acetyllysine substrates bearing a negatively charged α-carboxylate group.
“We recently reported the X-ray crystal structures of both catalytic domains (CDs) of HDAC6, showing that a conserved active site lysine serves as a gatekeeper in CD1, in that it dictates specificity for carboxy-terminal acetyllysine substrates bearing a negatively charged α-carboxylate group17.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Hai, Y. & Christianson, D. W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12, 741–747 (2016). source
Not checked in the free run.
May combine two claims.
PremisecitationSelective inhibition of PDAC activity in HeLa cells increases N8-acetylspermidine levels but not acetylated histone levels, so PDAC activity is distinct from HDAC activity.
“Selective inhibition of PDAC activity in HeLa cells increases N8-acetylspermidine levels but not acetylated histone levels, so PDAC activity is distinct from HDAC activity11.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Marchant, P. et al. A selective inhibitor of N8-acetylspermidine deacetylation in mice and HeLa cells without effects on histone deacetylation. Arch. Biochem. Biophys. 273, 128–136 (1989). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe positive charge of the N1-amino group of N8-acetylspermidine contributes to, but is not critical for, enzyme-substrate recognition.
“In addition, given the attenuated catalytic activity measured for N1,N8-diacetylspermidine, we concluded that the positive charge of the N1-amino group of N8-acetylspermidine contributed to, but was not critical for, enzyme–substrate recognition.”
Quote in the paperSubstantial claim- Rests on an assumption: The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
May combine two claims.
Interpretationown dataThe amino group of the substrate can be located at N4 or N5 but not at N3.
“Even so, the amino group could be located at N4 or N5, based on the substantial catalytic activity measured with acetylcadaverine and acetylputrescine. However, the amino group could not be at N3, based on the lack of substantial catalytic activity with N1-acetylspermidine and N-(3-aminopropyl)acetamide.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe ΨDAC domain of HDAC10 has no known catalytic function, although it may play a role in directing cytoplasmic enrichment.
“The ΨDAC domain of HDAC10 has no known catalytic function, although it may play a role in directing cytoplasmic enrichment19.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Tong, J. J., Liu, J., Bertos, N. R. & Yang, X. J. Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain. Nucleic Acids Res. 30, 1114–1123 (2002). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe E274-N4 separation is too long for a hydrogen bond but sufficiently close for a favourable electrostatic interaction.
“Although this interatomic separation was too long for a hydrogen bond interaction, it was sufficiently close for a favourable electrostatic interaction.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBoth gatekeeper E274 and the 310-helix ηA2 insertion promote PDAC activity and suppress HDAC activity.
“Therefore, both gatekeeper E274 and the 310-helix ηA2 insertion promote PDAC activity and suppress HDAC activity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHDAC6 is known to interact with and deacetylate MSH2 in vivo.
“Intriguingly, however, we demonstrated that the MSH2-based substrate GAK(ac)NLQ is efficiently deacetylated by HDAC6 (Supplementary Table 1 and Supplementary Fig. 3), which is also known to interact with and deacetylate MSH2 in vivo33.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Zhang, M. et al. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol. Cell 55, 31–46 (2014). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe steric protrusion formed by the ηA2 segment favours binding of long acetylpolyamine substrates and disfavours binding of shorter acetyllysine substrates.
“The steric protrusion formed by this segment favours the binding of long acetylpolyamine substrates (Fig. 3c) and disfavours the binding of shorter acetyllysine substrates (Fig. 4).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe gatekeeper is necessary but not sufficient for full activity and selectivity; both zHDAC10 and zHDAC6 CD1 have additional steric bulk opposite the gatekeeper that further constricts the active site.
“This gatekeeper is necessary but not sufficient for full activity and selectivity: both zHDAC10 and zHDAC6 CD1 have additional steric bulk opposite the gatekeeper that further constricts the active site.”
Quote in the paperSubstantial claimMay combine two claims.
Premiseown dataThe strict substrate regioselectivity of HDAC10 for N8-acetylspermidine contrasts with the broad substrate specificity of bacterial APAH, which has a glutamate residue (E117) to stabilize the positively charged N4 amino group through a salt bridge.
“The strict substrate regioselectivity of HDAC10 for N8-acetylspermidine contrasts with the broad substrate specificity of bacterial APAH, which has a glutamate residue (E117) to stabilize the positively charged N4 amino group through a salt bridge (Supplementary Fig. 7).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationE274 of zHDAC10 is conserved in HDAC10 orthologues as a gatekeeper to establish specificity for a cationic substrate, just as gatekeeper K330 is conserved in zHDAC6 CD1 to establish specificity for an anionic substrate.
“Our enzymological and X-ray crystallographic results suggest that E274 of zHDAC10 is conserved in HDAC10 orthologues as a gatekeeper to establish specificity for a cationic substrate, just as gatekeeper K330 is conserved in the corresponding position of zHDAC6 CD1 to establish specificity for an anionic substrate17.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Hai, Y. & Christianson, D. W. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12, 741–747 (2016). source
Not checked in the free run.
May combine two claims.
PremisecitationKnockdown or inhibition of HDAC10 blocks autophagy in a panel of neuroblastoma cell lines, sensitizing these cells to doxorubicin.
“However, the knockdown or inhibition of HDAC10 blocks autophagy in a panel of neuroblastoma cells lines, thereby sensitizing these highly malignant cells to the cytotoxic drug doxorubicin32.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Oehme, I. et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl Acad. Sci. USA 110, E2592–E2601 (2013). source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataInitial phases from the Phaser solution for the zHDAC10Δ (Y307F)-AAT complex were judged correct based on the initial electron density map, in which much of the omitted ΨDAC domain was clearly visible.
“Initial phases from the Phaser solution were judged to be correct based on the initial electron density map, in which much of the omitted ΨDAC domain was clearly visible.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe quality of each crystallographic model was verified with PROCHECK and MolProbity.
“The quality of each model was verified with PROCHECK and MolProbity4344.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [43] Laskowski, R. A., MacArthur, M. W., Moss, D. S. & Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993). source
Not checked in the free run.
- cites [44] Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D66, 12–21 (2010).
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo statistical methods were used to predetermine the sample size.
“No statistical methods were used to predetermine sample size.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenA standard curve using Fluor de lys deacetylated standard was used to calculate enzyme activity.
“A standard curve using Fluor de lys deacetylated standard (Enzo Life Sciences) was used to calculate enzyme activity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRamachandran statistics showed that all residues in the crystallographic models adopted allowed conformations.
“Ramachandran statistics showed that all residues adopted allowed conformations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSpermidine is a key factor in autophagy; increased levels of endogenous or exogenous spermidine induce autophagy and extend lifespan in a variety of cell types, including human immune cells.
“The polyamine spermidine is also a key factor in autophagy and increased levels of endogenous or exogenous spermidine induce autophagy and extend lifespan in a variety of cell types, including human immune cells3637.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [36] Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009). source
Not checked in the free run.
- cites [37] Minois, N. Molecular basis of the 'anti-aging' effect of spermidine and other natural polyamines – a mini-review. Gerontology 60, 319–326 (2014). source
Not checked in the free run.
May combine two claims.
PremisecitationHDAC10 protects cancer cells from chemotherapeutic drugs by mediating autophagy; upregulation of HDAC10 is a marker of poor outcome for advanced stage neuroblastoma patients.
“Recently, it has been demonstrated that HDAC10 protects cancer cells from chemotherapeutic drugs by mediating auto-phagy, a survival response to the cellular damage and metabolic stress induced by cytotoxic drugs; indeed, the upregulation of HDAC10 is a marker of poor outcome for advanced stage neuroblastoma patients32.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Oehme, I. et al. Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc. Natl Acad. Sci. USA 110, E2592–E2601 (2013). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataActivity assays were performed in triplicate at room temperature.
“Assays were performed at room temperature in triplicate.”
- Also stated in: § Activity assays · plain
“Assays were performed in triplicate.”
- Also stated in: § Activity assays · plain
“Assays were performed in triplicate at room temperature.”
Quote in the paperNot a substantial claim- Also stated in: § Activity assays · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationInhibition of ornithine decarboxylase reduces cellular polyamine levels and suppresses autophagy in eukaryotic cells, thereby attenuating infection by Trypanosoma cruzi.
“Recent studies show that the inhibition of ornithine decarboxylase, which utilizes arginase-derived ornithine to generate putrescine, reduces cellular polyamine levels and suppresses autophagy in eukaryotic cells, thereby attenuating infection by Trypanosoma cruzi38.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Vanrell, M. C. et al. Polyamine depletion inhibits the autophagic response modulating Trypanosoma cruzi infectivity. Autophagy 9, 1080–1093 (2013). source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataDeacetylation products were quantified using standard curves generated from the mass signals of the corresponding deacetylated polyamines and peptides.
“The deacetylation products were detected by LC–MS using a Waters SQD equipped with an Acquity UPLC (Waters, Milford, MA, USA) and quantified by using the standard curves generated from the mass signals of the corresponding deacetylated polyamines and peptides.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningGiven HDAC10 is a PDAC with catalytic specificity for hydrolysis of N8-acetylspermidine to yield spermidine and acetate, it is possible that the functions of HDAC10 and spermidine in autophagy are linked.
“Given that HDAC10 is a PDAC with catalytic specificity for the hydrolysis of N8-acetylspermidine to yield spermidine and acetate, it is possible that the functions of HDAC10 and spermidine in autophagy are linked.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The Y307F mutation and proteolytic truncation used to crystallize zHDAC10 do not alter the active-site structure or substrate specificity determinants observed in the crystal structure.
“Both proteolysis and the introduction of the deactivating Y307F mutation facilitated crystallization.”
The paper relies on this without support.
The recombinant full-length HDAC10 enzymes used in kinetics reflect the catalytic properties of native HDAC10 in cells.
“we prepared full-length recombinant HDAC10 from human (H. sapiens, hHDAC10) and zebrafish (D. rerio, zHDAC10).”
The paper relies on this without support.
The crystal structure of the zHDAC6 CD2–RGK(ac)-AMC complex is a suitable template for modeling the zHDAC10–substrate complex.
“A model of the zHDAC10–substrate complex was prepared by superimposing the crystal structure of the zHDAC6 CD2–RGK(ac)-AMC complex (PDB 5EFN) on the crystal structure of the closely related deacetylase domain of zHDAC10.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HDAC10 did not show significant conversion of any of the substrates tested.
“The second class IIb enzyme, HDAC10, did not show significant conversion of any of our substrates, which is in agreement with a recent report demonstrating the ability of HDAC10 to deacylate polyamines rather than lysine residues (Hai et al., 2017).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Hai et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting residue numbering for the ηA2 helix
MinorThe structural description identifies the helix as P23ACE, placing alanine at residue 24. The mutant-construction description identifies the same helix region as D24PACEI29, placing aspartate at residue 24 and proline at residue 25.
“a unique one-turn 310-helix ηA2 (P23ACE) resulting from a two-residue insertion plus a two-residue mutation in the L1 loop relative to zHDAC6”
“The zHDAC10 ΔηA2 mutant was prepared by by swapping the helix ηA2 region (D24PACEI29) with a tetrapeptide segment (S461HHP464) from the corresponding zHDAC6 CD2 L1 loop.”
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- Authors
- Hai, Y., Shinsky, S. A., Porter, N. J., & Christianson, D. W.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Christianson, David W.
- Venue
- Nature Communications
- Published
- 2017-05-18
- Volume
- 8
- Issue
- 1
- Pages
- 15368-15368
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5454378
- OpenAlex
- W2615685872
- Semantic Scholar
- f01f17d812145f40fee03a34b74d9d44c43e2959
- Cited by
- 200
- References
- 54
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 24 · 2023: 25 · 2022: 23 · 2021: 24 · 2020: 24 · 2019: 21 · 2018: 19 · 2017: 1
- FWCI
- 7.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM049758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HDAC10, polyamine metabolism, spermidine, spermine, crystal structure, transition-state inhibitors, active site specificity, autophagy, cancer chemotherapy, zebrafish
- MeSH terms
- Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Amino Acid Sequence, Animals, Cloning, Molecular, Histone Deacetylases, Humans, Isoenzymes, Kinetics, Models, Molecular, Protein Binding, Recombinant Proteins, Spermidine, Spermine, Substrate Specificity, Zebrafish, Gene Expression, Sequence Alignment, Sequence Homology, Amino Acid, Crystallography, X-Ray, Catalytic Domain, Zebrafish Proteins, Protein Interaction Domains and Motifs
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